Field of the Invention
The present invention relates to the field of retropharyngeal instillation of a medicament and particularly to a method and system for the administration of a pulmonary surfactant by atomization.
Discussion of the Background
Administration of a medicament in the lungs is often faced with the problem of finding the right balance between the efficacy and the invasiveness of the treatment. This is particularly difficult with infants (hereinafter the term neonates is used as synonymous of infants). Preterm neonates may be affected by nRDS (neonatal Respiratory Distress Syndrome), a lung disease due to generalized immaturity which causes the lack of pulmonary surfactant. For many years, nRDS has been treated by administration of exogenous pulmonary surfactants as bolus through endotracheal instillation to the intubated pre-term neonates kept under mechanical ventilation. Although this treatment is very effective, as proven by the reduced mortality, it may present some drawbacks which are intrinsic to the mechanical ventilation (volu/barotrauma) and to the intubation procedure which is anyway invasive.
In view of the potential complications associated with intubation and mechanical ventilation, attention has been focused on different approaches of administration of exogenous pulmonary surfactants. In particular, as a possible respiratory support, use of non-invasive ventilation procedures such as early nasal Continuous Positive Airway Pressure (nCPAP), that delivers air into the lungs through specifically designed nasal devices such as masks, prongs or tubes, has been introduced in neonatal intensive care.
Following this orientation, in the last fifteen years great attention has also been paid to finding an alternative way for pulmonary surfactant administration. Most of the performed studies have been focused on the administration of nebulized surfactant (i.e. particles with a mass diameter<10 μm) by means of commercial nebulizers connected to the ventilator circuit, based on the hypothesis that a gentler and more gradual administration should prevent the high cerebral blood fluctuation that may occur with bolus administration (See e.g. Mazela J, Merrit T A, Finner N N “Aerosolized surfactants” Curr Opin Pediatr. 2007; 19(2): 155; or Mazela J, Polin R A “Aerosol delivery to ventilated newborn infants: Historical challenges and new directions” Eur J Pediatr. 2011:1-12; or Shah S “Exogenus surfactant: Intubated present, nebulized future?” World Journal of Pediatrics. 2011; 7(1): 11-5, both of which are incorporated herein by reference in their entireties). Albeit the surfactant results more homogenously distributed, the improvements in the lung functionalities obtained in the different studies are very contrasting and they do not evidence the effectiveness of the nebulization approach. In other studies surfactant nebulization system was connected to non-invasive ventilator settings (i.e. CPAP through nasal prongs); in these conditions the amount of nebulized surfactant that reached the lung appeared to be negligible (less than 20%). Moreover nebulized surfactant administered during CPAP has no conclusive beneficial impacts on lung functionality as shown in pilot studies on preterm neonates (see e.g. Berggren E, Liljedhal M, Winbladh B, Andreasson B, Curstedt T, Robertson B, et al “Pilot study of nebulized surfactant therapy for neonatal respiratory distress syndrome” Acta Paediatrica 2000; 89 (4): 460-4; or Firmer N N, Merritt T A, Bernstein G, Job L, Mazela J, Segal R “An open label, pilot study of Aerosurf combined with nCPAP to prevent RDS in preterm neonates” Journal of aerosol medicine and pulmonary drug delivery. 2010; 23(5): 303-9; or Jorch G, Hartl H, Roth B, Kribs A, Gortner L, Schaible T, et al “Surfactant aerosol treatment of respiratory distress syndrome in spontaneously breathing premature infants” Pediatr Pulmonol. 1997; 24(3):222-4, all of which are incorporated herein by reference in their entireties). The studies are very variable and the authors apply different conditions with reference to several parameters, e.g.: 1) placement and type of aerosol generator, 2) mode of ventilation, 3) humidity, 4) air flow, 5) particle size, 6) nRDS models, 7) surfactant dilution, etc. Therefore it is difficult to make a proper comparison among them. However known systems do not generally prove to be very effective.
Moreover, when an aerosolized surfactant is administered with a nebulizer through a mask and not synchronized with the neonate' breath, some part can be exhaled during expiration and either deposits into the upper airways or tubing/connections or it is exhaled by the expiratory limbs. Moreover, the delivery of nebulised surfactant adds dead-space to the breathing circuits and, considering that preterm newborns may have a tidal volume of 1 ml or even less, this can promotes CO2 retention that, eventually, could become dangerous if a final situation of hypercapnia is achieved.
An interesting approach that could partially mitigate the above risk has been proposed by Wagner et al (Wagner M H, Amthauer H, Sonntag J, Drenk F, Eichstädt H W, Obladen M “Endotracheal surfactant atomization: an alternative to bolus instillation?” Crit Care Med. 2000; 28(7):2540, which is incorporated herein by reference in its entirety) showing encouraging results. It is based on a modified tracheal tube with an atomizer inserted at the tip of the tube which produces particles, that have a SMD (Souter Mean Diameter)>100 μm, only during inspiration (identified by an operator). The choice of putting the atomizer directly into the tube has been technologically challenging.
The promising results of the Wagner approach are probably due to the bigger dimensions of the particles which allow the distribution and absorption of the pulmonary surfactant similar to the mechanisms involved in the bolus administration. In particular, it can be hypothesized that big particles will deposit on more central airways, being able to reach the non-expanded alveoli by diffusion gradient, Marangoni effect and capillarity, while, on the contrary, the small nebulized particles, which are able to pass through the upper airways, are likely to be either exhaled during expiration or being deposited into the already opened alveoli which produces the airflow during breathing, without reaching the attelectatic region of the lung and contributing to an even more inhomogeneous distribution of lung time constants. Another advantage of Wagner is that the pulmonary surfactant is administered during inspiration phase only and this helps in better controlling the quantity of medicament effectively delivered (with improvements in terms of saving and clinical results).
A drawback of Wagner is that the tube must reach the trachea (where the nebulizer is placed), in order to be able to deliver the big sized particles which would be filtered out by the upper airways, and this procedure is invasive and can cause problems, in particular for neonates. On the other hand, all known prior art systems implementing a non-invasive (i.e. not entering the tracheal tube) delivery method are capable of administering only small sized particles which are able to overcome the outer barrier, but are less efficient in reaching all the lung regions needing treatment.
Furthermore, according to Wagner's experiment, the “synchronization” of the delivery of medicament with the inspiration rhythm is done manually, which is not ideal for obvious reasons including a waste of the product. On the other hand all attempts known in the art for implementing such synchronization, for example those described in EP 692 273, which is incorporated herein by reference in its entirety, depend on the presence of devices such as a mechanical ventilator. However, this solution needs connections to the airway of the newborn, adding dead space and mechanical load to the patient's breathing.
For all these reasons, an improved non-invasive method and system for administering the exogenous surfactant which is capable of combining the advantages of big size particle nebulization with proper automatic synchronization of the delivery would be greatly appreciated.